Gonadotropin Releasing Hormone (GnRH, or it is also called Luteinizing Hormone Releasing Hormone: LHRH, hereinafter referred to as “GnRH”) is a peptide consisting of 10 amino acids: pGlu-His-Trp-Ser-Tyr-Gly-Leu-Arg-Pro-Gly-NH2), which is secreted from the hypothalamus. GnRH secreted into hypophyseal portal vein promotes the production and secretion of gonadotropin of anterior pituitary hormones, Luteinizing Hormone: LH and Follicle Stimulating Hormone: FSH, via the receptors which are considered to exist in the anterior lobe of the pituitary, GnRH receptor. These gonadotropins affect gonad, ovary and testis, to promote the follicular growth, ovulation and luteinization and spermatogenesis and also promote the production and secretion of sex hormones such as estrogen, progesterone and androgen (see Non-patent reference 1). Accordingly, antagonists specifically and selectively acting on the GnRH receptors should control the activities of GnRH and control the production and secretion of gonadotropin and sex hormones, and therefore, are expected to be useful as an agent for the prevention or treatment of sex hormone-dependent diseases.
As an agent inhibiting the function of GnRH receptor, GnRH receptor superagonists (hereinafter referred to as “GnRH superagonist”) have been used as agents for the treatment of sex hormone-dependent diseases such as prostatic cancer, breast cancer and endometriosis and the like. The GnRH superagonists bind GnRH receptors and exert an initial temporary gonadotropin secretion-stimulating effect so-called “flare-up phenomenon”, and then suppress the function by causing gonadotropin depletion and GnRH receptor down-regulation to suppress. Therefore, the GnRH receptor superagonists have a problem that the disease becomes exacerbated transiently by the initially promoted secretion of gonadotropin. On the other hand, the suppression mechanism of GnRH receptor antagonists (hereinafter referred to as “GnRH antagonist”) is an inhibition of the binding to GnRH receptors, and therefore, are expected to exert promptly suppressive effects without secretion of gonadotropin. In these years, as GnRH antagonists, peptidic GnRH antagonists such as abarelix and cetrorelix have been developed and used for the treatment of prostatic cancer, infertility and the like. However, since these peptidic GnRH antagonists have bad oral absorbability, they have to be subcutaneously or intramuscularly administered. Thus, development of a non-peptidic GnRH antagonist which can be orally administered wherein local reactivity at injected sites can be reduced and the dosages can be flexibly adjusted is desired (see Non-patent reference 2).
As fused imidazolidine derivatives, various compounds are illustrated as anticancer agents in Patent reference 1, feeding control agents in Patent reference 2, antigastric ulcers in Non-patent reference 3 and antimicrobials in Non-patent reference 4, respectively. However, in any of these references, there are no description or suggestion about that a fused imidazolidine derivative of the present invention has a GnRH antagonistic activity.    Non-patent reference 1: Hyojun Seirigaku (Standard Physiology), Edition 5, Igakusyoin, pp. 882-891.    Non-patent reference 2: Sanka to Fujinka (Obstetrics and Gynecology), 2004, Vol. 71, No. 3, pp. 280-285 and 301-307.    Non-patent reference 3: Mario Bianch et. al. and 4 persons, Eur. J. Med. Chem., Chimica Therapeitica, 1981, Vol. 16, No. 4, pp. 321-326.    Non-patent reference 4: V. K. Agrawal et. al. and 2 persons, Indian Journal of Chemistry, May 1981, Vol. 20B, pp. 398-400.    Patent reference 1: International publication No. WO2006/10594 pamphlet.    Patent reference 2: International publication No. WO2005/35498 pamphlet.